Biodegradable implant and method for manufacturing same

ABSTRACT

This invention relates to a biodegradable implant including magnesium, wherein the magnesium contains, as impurities, (i) manganese (Mn); and (ii) one selected from the group consisting of iron (Fe), nickel (Ni) and mixtures of iron (Fe) and nickel (Ni), wherein the impurities satisfy the following condition: 0&lt;(ii)/(i)≦5, and an amount of the impurities is 1 part by weight or less but exceeding 0 parts by weight based on 100 parts by weight of the magnesium, and to a method of manufacturing the same.

TECHNICAL FIELD

The present invention relates to a biodegradable implant and a method ofmanufacturing the same, and more particularly to a biodegradableimplant, whose biodegradation rate is easily controlled, the strengthand an interfacial force to bone tissue of which are high, in which arate of bone formation is increased, and that has simultaneouslyimproved corrosion resistance and mechanical properties, and to a methodof manufacturing the same.

BACKGROUND ART

Typical materials used in implants to be used in medical treatmentinclude metal, ceramic and polymer. Among these, metallic implants havesuperior mechanical properties and processability. However, metallicimplants are disadvantageous because of stress shielding, imagedegradation and implant migration. Also, ceramic implants have superiorbiocompatibility compared to the other implants. However, ceramicimplants are easily broken by external impact, and are difficult toprocess. Also, polymeric implants have relatively weak strength comparedto the other implant materials.

Recently, porous implants are being developed which may accelerate theformation of bone tissue upon insertion into the human body and maydecrease Young's modulus to prevent stress shielding. However, suchporous implants have low mechanical strength and are weak to externalimpact. Also, research and development is being carried out intobiodegradable implants which need not be removed after being insertedinto the human body to achieve their desired purpose. The study ofmedical applications using such a biodegradable material has alreadybegun since the middle of the 1960s and is mainly focused on usingpolymers such as polylactic acids (PLA), polyglycolic acid (PGA) or acopolymer thereof including PLGA. However, biodegradable polymers havelow mechanical strength, produce acids upon decomposition, and have thedisadvantage that it is difficult to control their biodegradation rate,and thus they have limited applications. In particular, thebiodegradable polymers are difficult to apply to orthopedic implantsthat have to withstand a strong load or dental implants because of theproperties of polymers having low mechanical strength. Hence, somebiodegradable materials are being studied to overcome the problems ofthe biodegradable polymers. Typical examples thereof include ceramicsuch as tri-calcium phosphate (TCP), combination materials ofbiodegradable polymer and biodegradable hydroxyapatite (HA), etc.

However, mechanical properties of such materials are not much higherthan those of biodegradable polymers. In particular, poor impactresistance of the ceramic material is regarded as very disadvantageousin a biomaterial. Also, the actual usability of such materials is opento question, because it is difficult to control the biodegradation rate.

Meanwhile, biodegradable implants should be very strong because part orall of it have to withstand a load when used into the human body. Inorder to ensure high strength, a biodegradable implant is furthersubjected to additional processes including rapid cooling, extrusion,and heat treatment so that the framework of the implant is made fine andinternal residual stress should be controlled. Also, the alloycomposition of a metal used for a biodegradable implant should beappropriately designed by changing constituent elements or contentthereof. As such, changing the alloy composition may be typicallyperformed by adjusting the amounts of the elements that are added. Asthe amounts of elements added to the alloy increase, mechanical strengthis enhanced.

However, when the amounts of added elements are increased, the metal forthe implants may easily create a galvanic circuit that increases thecorrosion rate attributable to an increase in the non-uniformity of thecomposition thereof and the non-uniformity of a fine framework,undesirably increasing the corrosion rate of implants. Hence, it is verydifficult to design alloy materials which have high strength and lowbiodegradation rate to be applied to implants.

DISCLOSURE Technical Problem

Accordingly, the present invention has been made keeping in mind theabove problems occurring in the related art, and an object of thepresent invention is to provide a biodegradable implant whosebiodegradation rate may be controlled.

Another object of the present invention is to provide a biodegradableimplant which may overcome problems of conventional porous implants suchas low mechanical strength and poor impact resistance.

A further object of the present invention is to provide a biodegradableimplant whose corrosion resistance and mechanical properties have beensimultaneously improved.

Still a further object of the present invention is to provide abiodegradable implant in which a rate of bone formation may beincreased, and with the passing of a predetermined period of time aftersurgery, a biodegradable metal material charged in pores has disappearedand an osseous replacement has taken place.

Technical Solution

In order to accomplish the above objects, an aspect of the presentinvention provides a biodegradable implant comprising magnesium, whereinthe magnesium contains as impurities (i) manganese (Mn); and (ii) oneselected from the group consisting of iron (Fe), nickel (Ni) andmixtures of iron (Fe) and nickel (Ni), wherein the impurities satisfythe following condition: 0<(ii)/(i)≦5, and an amount of the impuritiesis 1 part by weight or less but exceeding 0 parts by weight based on 100parts by weight of the magnesium.

In addition, another aspect of the present invention provides a methodof manufacturing a biodegradable implant, comprising a) providingmagnesium containing as impurities (i) manganese (Mn); and (ii) oneselected from the group consisting of iron (Fe), nickel (Ni) andmixtures of iron (Fe) and nickel (Ni), wherein the impurities satisfythe following condition: 0<(ii)/(i)≦5, and an amount of the impuritiesis 1 part by weight or less but exceeding 0 parts by weight based on 100parts by weight of the magnesium; and b) forming the magnesium.

In addition, another aspect of the present invention provides abiodegradable implant, comprising a magnesium alloy represented byChemical Formula 1 below comprising based on the total weight thereof,23 wt % or less but exceeding 0 wt % of Ca; 10 wt % or less butexceeding 0 wt % of X; and a remainder of Mg:

Mg—Ca—X   <Chemical Formula 1>

wherein X is Mn or Zn

In addition, another aspect of the present invention provides a methodof manufacturing a biodegradable implant, comprising i) providing themagnesium alloy; and ii) forming the magnesium alloy.

In addition, another aspect of the present invention provides a methodof manufacturing a biodegradable implant, comprising applying ultrasoundto the biodegradable implant comprising magnesium.

In addition, another aspect of the present invention provides abiodegradable implant, comprising, based on the total weight thereof, 10wt % or less but exceeding 0 wt % of manganese; 1 wt % or less butexceeding 0 wt % of iron; and a remainder of a metal comprisingmagnesium.

In addition, another aspect of the present invention provides abiodegradable implant, comprising, based on the total weight thereof, 90wt % or less but exceeding 0 wt % of magnesium oxide (MgO); and aremainder of a metal comprising magnesium.

Advantageous Effects

According to the present invention, a biodegradable implant can beadvantageously present for a long period of time in vivo because itsbiodegradation rate is controlled to be very low.

Also according to the present invention, in the case where thebiodegradable implant includes a porous structure, blood vessels thatpass through pores are formed, thus increasing the rate of boneformation and decreasing Young's modulus thereby reducing stressshielding.

Also according to the present invention, the biodegradable implant canhave enhanced mechanical strength and impact resistance.

Also according to the present invention, the biodegradable implant canbe simultaneously improved in terms of corrosion resistance andmechanical properties.

Thus, the implant according to the present invention is adapted to beused in bone replacements or treatment for bone, and can be used fororthopedics, dental care, plastic surgery or blood vessels.

DESCRIPTION OF DRAWINGS

FIG. 1 is a graph showing the hydrogen evolution amount in relation tothe immersion time of the implant samples of Example 1 and 2 andComparative Examples 1;

FIG. 2 is a graph showing results of evaluating mechanical strength ofthe implant samples of Examples 3 and 4 and Comparative Example 3 beforeextrusion;

FIG. 3 is a graph showing results of evaluating mechanical strength ofthe implant samples of Examples 3 and 4 and Comparative Example 3 afterextrusion;

FIG. 4 is a graph showing the hydrogen evolution rate in relation to theimmersion time of the implant samples of Examples 3 and 4 andComparative Example 3;

FIG. 5 is a graph showing the hydrogen evolution rate in relation to theimmersion time of the implant samples of Examples 4 to 6.

FIG. 6 is a graph showing the hydrogen evolution amount in relation tothe immersion time of the implant samples of Examples 7 to 11 andComparative Examples 2 and 4;

FIG. 7 is a graph showing the hydrogen evolution amount in relation toZn content;

FIG. 8 is an electron microscope image showing the surface of theimplant sample of Example 7 immersed in abiomimetic solution for 61hours;

FIG. 9 is an image showing the surface of the implant sample of Example7 immersed in a biomimetic solution for 61 hours as analyzed using EDS;

FIG. 10 is an image showing the implant sample of Example 7 which isimmersed in a biomimetic solution for 61 hours and from which acorrosion material was removed;

FIG. 11 is an image showing the cross-section of the implant sample ofExample 7 immersed in a biomimetic solution for 61 hours;

FIG. 12 is an enlarged image of the image of FIG. 11;

FIG. 13 is of WDS (JXA-8500F, available from JEOL) images showing theimplant sample of Example 7 immersed in a biomimetic solution for 61hours;

FIG. 14 is an image showing the cross-section of the implant sample ofExample 8 immersed in abiomimetic solution for 61 hours;

FIG. 15 is of WDS (JXA-8500F, available from JEOL) images showing theimplant sample of Example 8 immersed in a biomimetic solution for 61hours;

FIG. 16 is a graph showing the hydrogen evolution rate in relation tothe immersion time in two implant samples of Example 8 one of which istreated with ultrasound and the other one of which is not treated withultrasound after which they are immersed in a biomimetic solution;

FIG. 17 is a graph showing the hydrogen evolution amount in relation tothe immersion time in the implant sample of Example 8 treated withultrasound and then immersed in a biomimetic solution;

FIG. 18 is a graph showing the hydrogen evolution amount in relation tothe immersion time of the implant samples of Examples 12˜14;

FIG. 19 is of images showing the size of crystal grains of the implantsample of Example 14 before extrusion;

FIG. 20 is a graph showing the hydrogen evolution amount in relation tothe immersion time before and after extrusion of the implant sample ofExample 14; and

FIG. 21 is a photograph showing swelling due to the generation ofhydrogen gas in a rat into which the implant sample of ComparativeExample 4 is inserted.

BEST MODE

Hereinafter, a detailed description will be given of the presentinvention.

I. Biodegradable Implant Containing Impurities

According to the present invention, a biodegradable implant comprisesmagnesium (Mg), wherein the Mg contains, as impurities (i) Mn and (ii)one selected from the group consisting of Fe, Ni and mixtures of Fe andNi, wherein the impurities satisfy the following condition:0<(ii)/(i)'5, and an amount of the impurities is 1 part by weight orless but exceeding 0 parts by weight based on 100 parts by weight of themagnesium.

Preferably, the impurities satisfy the following condition:0<(ii)/(i)≦0.5. If the impurities satisfy the condition, thebiodegradation rate is controlled to be maximally low thus increasingcorrosion resistance. Thereby, implants may be present for a longerperiod of time in vivo.

When Ni and Mn are contained in the impurities, Ni causes an allergicreaction in the human body and increases the corrosion rate of pure Mg.Hence, Ni content is preferably 100 ppm or less, and more preferably 50ppm or less.

Also, the Mg may further include aluminum (Al) as an impurity.

According to the present invention, there may be provided abiodegradable implant resulting from charging Mg containing the aboveimpurities in the pores of a porous structure.

The pores of the porous structure preferably have a size of 200˜500 μm,and the pore size may be adjusted depending on the application fieldusing methods typically used in the art. If the pore size falls withinthe above range, it is easy to allow blood vessels responsible forsupplying nutrients, minerals and ions to pass through the pores.

The porous structure may have a porosity of 5˜95%. The porosity means avolume ratio of pores relative to total volume. In the case where thestrength required of a target is high, the porosity may be decreased sothat the strength of a porous structure is enhanced. For example, thecase where a porous structure is made of tantalum having high strengthor merely functions to fill the cavities of lost bone, high porositythereof does not cause problems.

The porous structure may comprise one or more selected from the groupconsisting of a metal, a ceramic, and a polymer. In the case where theporous structure is made of a metal, one or more selected from the groupconsisting of titanium or a titanium alloy, a cobalt-chromium alloy andstainless steel may be used. In the case where the porous structure ismade of a ceramic, one or more selected from the group consisting ofcalcium phosphate, alumina, zirconia and magnesia may be used. In thecase where the porous structure is made of a polymer, one or moreselected from the group consisting of polyethylene, polylactic acids(PLA), polyglycolic acid (PGA) and a copolymer thereof including PLGAmay be used. As such, in the case where the porous structure maycomprise the above polymer, an acid that is biodegradable is generatedso that the pH may decrease. In the case of a polymer composite in whichpores are filled with Mg, Mg may increase the pH while it isdecomposing, and thus when the rate of decomposition of the polymer andMg is controlled, an additional effect of arbitrarily adjusting the pHin vivo may be expected.

According to the present invention, the biodegradable implant may beused for orthopedics, dental care, plastic surgery or blood vessels.Specifically, the above implant may be utilized for an interbody spacerfor the spine, a bone filler, a bone plate, bone pin, bone screw,scaffold, Stent and artificial dental root.

II. Method of Manufacturing the Biodegradable Implant ContainingImpurities

Below is a description of a method of manufacturing the biodegradableimplant according to the present invention.

According to the present invention, the method of manufacturing thebiodegradable implant comprises a) providing Mg containing as impurities(i) Mn and (ii) one selected from the group consisting of Fe, Ni andmixtures of Fe and Ni, wherein the impurities satisfy the followingcondition: 0<(ii)/(i)≦5, and an amount of the impurities is 1 part byweight or less but exceeding 0 parts by weight based on 100 parts byweight of the magnesium; and b) forming the magnesium.

In a), Mg is preferably provided in the form of being molten.Specifically, a) is performed by melting Mg in an inert gas atmospheresuch as argon (Ar) that does not react with Mg or in a vacuum. Also,providing the molten Mg in a) may be carried out using a variety ofprocesses, including a resistance heating process for generating heat byapplying electricity to a resistor, an induction heating process thatallows current to flow in an induction coil, or a laser- or focusedlight-based process. Among the above melting processes, a resistanceheating process is particularly useful. It is preferred that the moltenalloy (i.e. a melt) be stirred so that the impurities are well mixedwhen the Mg melts.

According to another embodiment of the present invention, in the casewhere there is provided a biodegradable implant obtained by filling thepores of a porous structure with the Mg alloy, a) may include a-1)preparing a porous structure; and a-2) filling the pores of the porousstructure with the Mg alloy.

In a-1), the porous structure may comprise one selected from the groupconsisting of a metal, a ceramic and a polymer.

a-1) is described below for the case when the porous structure isprepared using only a metal.

Specifically, a metal is prepared in the form of powder or a wire. Themetal powder or wire is prepared into a preform (a Green preform). Assuch, the preform may be obtained using a sintering process or amodified sintering process.

The production of the preform using a sintering process is as follows:first, metal powder or wire is placed in a vessel, or is pressed by anappropriate force of 100 MPa or less so as to have weak strength, afterwhich the metal having weak strength is maintained at a temperature of2/10˜9/10 of the melting point of the metal so that the powder or wirerespectively coheres thus obtaining a preform having mechanicalstrength.

Also, the production of the preform using a modified sintering processis as follows: first, metal powder or wire is placed in a conductivevessel such as graphite vessel, and high current is then applied to theconductive vessel so that heat is instantly generated on the contactportion of the metal powder or wire thus preparing a sintered body,which is then formed into a preform.

a-1) is described below for the case of using a metal and a polymer toprepare the porous structure.

Specifically, a metal is prepared in the form of powder or a wire.Subsequently, the metal powder or wire is mixed with a polymer, and inthe course of increasing the temperature, the polymer decomposes anddisappears at low temperature and the metal powder or wire is sinteredat high temperature, thus obtaining a preform having the appropriatemechanical strength. As such, the porosity and the strength of thesintered body are determined by the sintering temperature, the pressure,the ratio of the polymer and metal in the mixture, etc., and properconditions may be selected as necessary. The sintering temperature mayvary depending on the type of material used to prepare the porousstructure, and is typically set to the level of about 1/2˜9/10 of themelting point of the porous structure. Although sintering may occur evenin the absence of pressure, sintering may rapidly progress in proportionto an increase in pressure. However, as the pressure is higher, there isa need for additional costs including device cost and mold cost, andthus the appropriate pressure should be selected.

In addition to the above method, a-1) is described below for the case ofusing a metal and a polymer to prepare the porous structure.

Specifically, the surface of a polymer is plated with a precious metal,such as gold, platinum, and Pd. Subsequently, the polymer is removed,thus obtaining a metal porous structure having better biocompatibility.

a-1) is described below for the case of using an aqueous salt and ametal to prepare the porous structure.

Specifically, an aqueous salt and metal powder are mixed and then formedat high temperature, thus obtaining a preform. The aqueous salt mayinclude one or more selected from the group consisting of NaNO₂, KNO₂,NaNO₃, NaCl, CuCl, KNO₃, KCl, LiCl, KNO₃, PbCl₂, MgCl₂, CaCl₂ and BaCl₃.

Subsequently, the preform is pressed at a temperature of 2/10˜9/10 ofthe melting point of the metal powder. In the course of pressing, themetal powder coheres via migration of atoms to form a structure, and theaqueous salt is contained therein, thus obtaining a composite. When thecomposite is immersed in water, only the aqueous salt may dissolve,resulting in a metal porous structure having pores. Furthermore, a metalporous structure may be obtained by completely melting a metal materialand then injecting a foaming agent to generate gas.

a-1) is described below for the case when a polymer and an electrolytehaving metal ions are used to prepare the porous structure.

Specifically, the surface of a porous polymer is plated with a metalusing an electrolyte having metal ions. As such, the metal ions are notparticularly limited, but one or more selected from the group consistingof Ti, Co, Cr and Zr may be used. Subsequently, the temperature isincreased to remove the polymer, thereby obtaining a metal porousstructure.

a-2) is described below for the case when the porous structure isprepared using a ceramic.

Specifically, fine ceramic grains and a binder polymer are mixed. Theresultant mixture is applied on the surface of a backbone structure madeof a foaming agent such as polyurethane which is removable, and thendried thus preparing a porous structure. Thereafter, when thetemperature is increased, the polymer is combusted and removed at atemperature near the combustion temperature of the binder polymer. Whenthe temperature is further increased, the remaining ceramic grains aremutually sintered, resulting in a porous structure having mechanicalstrength.

As such, the fine ceramic grains may comprise one or more selected fromthe group consisting of hydroxyapatite (HA), zirconia and alumina.

a-1) may be a modification or combination of the above methods ofproducing the porous structure, or may be a method of forming a porousstructure having different porosities inside and outside by applying itto some of heterogeneous materials. The latter method enables theproduction of a porous structure the density of the inside of which ishigh because there are few or no pores and the porosity of the outsideof which is high so that the porosity is different at differentpositions. This method may be employed upon production of an implantthat may endure high external stress throughout its entirety whileinducing a high rate of bone formation on the surface of the implantFurthermore, the production of the porous structure as above is only anillustration among a variety of methods of producing a porous structure,and the scope of the present invention is not limited by variations ofthe methods of producing the porous structure.

a-2) may include one selected from the group consisting of immersing theporous structure in a molten Mg solution, allowing a molten Mg solutionto flow in the fixed porous structure so that pores are filledtherewith, and applying an external pressure of 1 atm or more in theabove two cases so that molten Mg is more easily charged in the pores ofthe porous structure. As such, in order to prevent the molten Mg fromsolidifying in the course of the pores being filled therewith, theporous structure may be heated or a variety of surface contaminants maybe removed so that the molten Mg is easily charged in the pores.

Also, a-2) may be as follows: Mg is vaporized at high temperature,preferably 700° C. or more, so that Mg vapor is deposited on the surfaceof the pores while passing through the pores of the porous structure,thus filling the pores of the porous structure with Mg.

Also, a-2) may be as follows: an Mg-containing salt is melted in aliquid, after which Mg is adsorbed on the surface of the pores of aporous structure while passing the porous structure through the liquid.

As another modification in addition to the above filling processes, onlypart of pores of the porous structure may be filled with the Mg alloy,instead of all of them being filled therewith. Specifically, the moltenMg is charged in the porous structure, after which high-pressure gas isblown into the porous structure or the porous structure is rotated orstirred before Mg is completely solidified. Thereby, non-solidified Mgis removed from the porous structure and only part of Mg may be leftbehind in the pores, thus obtaining a composite in which part of thepores is impregnated with Mg. In this case, a rate of charging Mg may bedifferently controlled at positions of the pores of the porousstructure.

As another modification, the application of Mg is controlled such thatMg is applied only to the surface of the backbone of the porousstructure and a predetermined portion of the pores may remain unfilled,and thereby additional effects are expected including it being easier toform bone by Mg while maintaining spaces wherein the fine blood vesselsnecessary to form bone may be easily formed in the implant.

In the case of a polymer having a melting point lower than that of Mg,when a porous structure is first prepared and then pores thereof arefilled with molten Mg, the polymer porous structure cannot maintain itsshape. Thus, the biodegradable polymer having a polymer and Mg may bemanufactured by mixing Mg powder and the polymer at a volume ratio of5:95 to 95:5, increasing the temperature to 150˜500° C. and applyingpressure in the range of 1 atm to 100 atm. The above conditions arepreferable for the manufacture of the polymer-Mg biodegradable implant,but under conditions falling outside of the above conditions, thepolymer-Mg biodegradable implant may also be formed. Thus it willinfringe the scope of the present invention to change the manufacturingconditions for manufacturing the polymer-Mg biodegradable implant.

The method of manufacturing the porous structure made of metal, ceramicand polymer, the method of filling pores of the porous structure with Mgalloy, and the method of manufacturing the Mg-filled polymerbiodegradable implant are merely illustrative in the present invention,and the scope of the present invention is not limited thereto.

In the method of manufacturing the biodegradable implant according tothe present invention, b) may be forming the molten Mg alloy forcontrolling a biodegradation rate using one or more selected from thegroup consisting of cooling, extrusion and metal processing.

The cooling process may be used to enhance the mechanical strength ofthe Mg alloy. Specifically, when Mg is melted in a), immersing acrucible including molten Mg in water may be utilized. Also, the moltenMg may be cooled by spraying an inert gas such as argon. The coolingprocess using spraying is performed at a much higher r ate thusobtaining a very fine framework. However, in the case where Mg is castin a small size, it should be noted that a plurality of pores (blackportion) be formed therein.

The extrusion process is used to make the framework of the Mg uniformand enhance mechanical performance. The extrusion process may beperformed at 300˜450° C. Furthermore, the extrusion of Mg may be carriedout in a ratio of reduction in the cross-sectional area before and afterextrusion (an extrusion ratio) of 10:1˜30:1. As the extrusion ratiobecomes higher, the fine framework of the extrusion material may becomeuniform, and defects caused upon casting may be easily removed. In thiscase, it is preferred that the capacity of an extrusion device beincreased.

The metal processing is not particularly limited so long as it is knownin the art. For example, molten Mg may be poured onto a mold processedto have a shape close to a shape of a final product and thus directlycast, or may be prepared into an intermediate material such as a rod ora sheet and then subjected to turning or milling, and also the Mg alloymay be forged at a higher pressure thus obtaining a final product.

III. Biodegradable Implant Represented by Mg—Ca—X

The biodegradable implant according to the present invention comprisesan Mg alloy which is represented by Chemical Formula 1 below andcomprises based on the total weight thereof, 23 wt % or less butexceeding 0 wt % of Ca, 10 wt % or less but exceeding 0 wt % of X, and aremainder of Mg.

Mg—Ca—S   <Chemical Formula 1>

In Chemical Formula 1, X is Mn or Zn.

When the Mg alloy falls within the above range, a biodegradable implantin which mechanical properties and corrosion resistance aresimultaneously improved and brittleness fractures do not occur may beprovided.

Also, the Mg alloy preferably comprises, based on the total weightthereof, 23 wt % or less but exceeding 0 wt % of Ca, 0.1˜5 wt % of X andthe remainder of Mg, and more preferably 23 wt % or less but exceeding 0wt % of Ca, 0.1˜3 wt % of X and the remainder of Mg. When the samecorrosion rate is embodied, the case where the amount of impurities islow is favorable for fear of the impurities causing side effects.

According to the present invention there may be provided a biodegradableimplant obtained by filling pores of a porous structure with the Mgalloy represented by Chemical Formula 1, comprising, based on the totalweight thereof, less than 23 wt % but exceeding 0 wt % of Ca, less than10 wt % but exceeding 0 wt % of X, and a remainder of Mg.

The size of pores of the porous structure is preferably 200˜500 Elm. Thepore size may be adjusted depending on the application field usingtypical methods of the art When the pore size falls within the aboverange, it is easy to allow blood vessels responsible for supplyingnutrients, minerals and ions to pass through the pores.

The porous structure may have a porosity of 5˜95%. The porosity is avolume ratio of pores relative to total volume. In the case where therequired strength of a target is high, the porosity is decreased so thatthe strength of the porous structure may be increased. For example, thecase where the porous structure is a metal such as tantalum having highstrength or merely functions to fill the cavities of lost bone, highporosity thereof does not cause problems.

The porous structure may be formed of one or more selected from thegroup consisting of a metal, a ceramic and a polymer. The metal mayinclude one or more selected from the group consisting of titanium or atitanium alloy, a cobalt-chromium alloy and stainless steel. The ceramicmay include one or more selected from the group consisting of calciumphosphate, alumina, zirconia and magnesia. The polymer may include oneor more selected from the group consisting of polyethylene, polylacticacids (PLA), polyglycolic acid (PGA) and a copolymer thereof such asPLGA. In the case where the porous structure is made with the abovepolymer, a biodegradable acid may be produced thus decreasing the pH. Assuch, in the case of a polymer composite comprising pores filled withthe Mg alloy, Mg may increase the pH while it is decomposing, and thusan additional effect of arbitrarily adjusting the pH in vivo via controlof the rate of decomposition of the polymer and Mg may be expected.

The biodegradable implant according to the present invention may be usedfor orthopedics, dental care, plastic surgery or blood vessels.Specifically, the above implant may be utilized for an interbody spacerfor the spine, a bone filler, a bone plate, bone pin, bone screw,scaffold, and artificial dental root

IV. Method of Manufacturing the Biodegradable Implant represented byMg—Ca—X

Below is a description of a method of manufacturing the biodegradableimplant according to the present invention.

The biodegradable implant according to the present invention ismanufactured by i) providing an Mg alloy represented by Chemical Formula1 below, comprising based on the total weight thereof less than 23 wt %but exceeding 0 wt % of Ca, less than 10 wt % but exceeding 0 wt % of X,and less than 100 wt % but exceeding 67 wt % of Mg; and ii) forming theMg alloy.

Mg—Ca—X   <Chemical Formula 1>

In Chemical Formula 1, X is Mn or Zn.

The description of the Mg alloy is as above and is omitted herein.

i) is preferably providing the Mg alloy in a molten state. Thedescription of i) is the same as that of a) and is thus omitted.

According to another embodiment of the present invention, in the casewhere there is provided a biodegradable implant resulting from fillingthe pores of a porous structure with the above Mg alloy, i) may comprisei-1) preparing a porous structure and i-2) filling the pores of theporous structure with the Mg alloy.

The description of i-1) and i-2) is the same as that of a-1) and a-2)and is thus omitted.

In the method of manufacturing the biodegradable implant according tothe present invention, may be forming the molten Mg alloy forcontrolling a biodegradation rate using one or more selected from thegroup consisting of cooling, extrusion and metal processing.

The description of ii) is the same as that of b) and is thus omitted.

V. Method of Manufacturing Biodegradable Implant Using Ultrasound

The present invention provides a method of manufacturing a biodegradableimplant, comprising applying ultrasound to the biodegradable implantcomprising Mg. When ultrasound is applied to the biodegradable implantcomprising Mg, the corrosion rate may increase in vivo, so that theimplant may disappear within a shorter period of time.

The biodegradable implant comprising Mg may be a porous structure,wherein Mg contains as impurities (i) Mn and (ii) one selected from thegroup consisting of Fe, Ni and mixtures of Fe and Ni, wherein theimpurities satisfy the following condition: 0</(i)≦5, and an amount ofthe impurities is 1 part by weight or less but exceeding 0 parts byweight based on 100 parts by weight of the magnesium. Also, thebiodegradable implant may include an Mg alloy represented by ChemicalFormula 1 below, comprising based on the total weight thereof, less than23 wt % but exceeding 0 wt % of Ca, less than 10 wt % but exceeding 0 wt% of X, and less than 100 wt % but exceeding 67 wt % of Mg.

Mg—Ca—X   <Chemical Formula 1>

In Chemical Formula 1, X is Mn or Zn.

The biodegradable implant according to the present invention may beadvantageously present in vivo for a long period of time because thebiodegradation rate is controlled to be very low. Also, in the casewhere the biodegradable implant according to the present inventionincludes a porous structure, blood vessels that pass through the poresare formed, thus increasing the rate at which bone is formed anddecreasing Young's modulus to thereby reduce stress shielding. Also, thebiodegradable implant according to the present invention may haveenhanced mechanical strength and impact resistance. Also, thebiodegradable implant according to the present invention may besimultaneously improved in terms of corrosion resistance and mechanicalproperties. Thus, the implant according to the present invention isadapted to be used in bone replacements or treatment for bone and may beused for orthopedics, dental care, plastic surgery or blood vessels.

VI. Biodegradable Implant Having Controlled Mn Content

The biodegradable implant according to the present invention comprises,based on the total weight thereof, 10 wt % or less but exceeding 0 wt %of Mn; 1 wt % or less but exceeding 0 wt % of Fe; and 99 wt % to lessthan 100 wt % of a metal comprising Mg. As such, the Mn content may beset to 0.3˜0.6 wt %.

In the biodegradable implant according to the present invention, Fe isfurther included as an impurity.

The biodegradable implant according to the present invention includes Mnin the above content range, which is bound with Fe contained in themetal comprising Mg thus decreasing a difference in potential to therebyreduce galvanic corrosion. Furthermore, Fe contained in the metalcomprising Mg is enclosed with Mn so that contact between Mg and Fe isblocked, thus preventing or reducing the corrosion.

Here, the metal comprising Mg may be pure Mg, Mg having a very smallamount of impurity, or an Mg alloy. This impurity X may be selected fromthe group consisting of zirconium (Zr), molybdenum (Mo), niobium (Nb),tantalum (Ta), titanium (Ti), strontium (Sr), chromium (Cr), manganese(Mn), zinc (Zn), silicon (Si), phosphorus (P) and nickel (Ni).

VII. Biodegradable Implant Comprising Magnesium Oxide

The biodegradable implant according to the present invention comprises,based on the total weight thereof, 90 wt % or less but exceeding 0 wt %of magnesium oxide (MgO); and 10 wt % to less than 100 wt % of a metalcomprising Mg.

When MgO is contained in the above amount in the biodegradable implantaccording to the present invention, the corrosion properties of thebiodegradable implant are controlled, thus preventing swelling due tohydrogen being generated upon insertion of the biodegradable implant invivo.

As the amount of MgO is higher in the biodegradable implant according tothe present invention, the corrosion of the metal comprising Mg may bereduced. However, it is very preferred that MgO be contained in theabove amount range.

The metal comprising Mg may be pure Mg, Mg having a very small amount ofimpurity, or an Mg alloy. This impurity X may be selected from the groupconsisting of zirconium (Zr), molybdenum (Mo), niobium (Nb), tantalum(Ta), titanium (Ti), strontium (Sr), chromium (Cr), manganese (Mn), zinc(Zn), silicon (Si), phosphorus (P) and nickel (Ni).

VIII. Biodegradable Implant Having Controlled Corrosion Properties viaExtrusion

The biodegradable implant according to the present invention may preventPCP (Preferred Crystallographic Pitting Corrosion) caused by coarsecrystal grains therein, using extrusion. Specifically, when crystalgrains are coarse, the probability of corrosion between the crystalgrains is high. The size of crystal grains is decreased via extrusion sothat the intervals between crystal grains are decreased, therebypreventing such corrosion.

As such, the ratio of reduction in the cross-sectional area before andafter extrusion (the extrusion ratio) is not particularly limited solong as it is 2:1 or more, but preferably exceeds 25:1 or 20:1.

Mode for Invention

The following examples which are set forth to illustrate but are not tobe construed as limiting the present invention, may provide a betterunderstanding of the present invention which is about the manufacturingof biodegradable implants comprising Mg or an Mg alloy for controllingthe biodegradation rate.

EXAMPLES 1, 2 AND COMPARATIVE EXAMPLE 1 Manufacturing of BiodegradableImplant Comprising Mg Alloy for Controlling Biodegradation RateComprising 1 Part by Weight or Less but Exceeding 0 Parts by Weight ofTotal of Impurities Including Mn, Fe and Ni based on 100 parts by weightof Mg and the Impurities Satisfying the Following Condition:0<{Fe+Ni}/Mn≦5

Fe, Ni, Al, Mn and Mg in the amounts shown in Table 1 below were chargedin a crucible having an inner diameter of 50 mm made of stainless steel(SUS 410). Subsequently, while Ar gas was allowed to flow around thecrucible so that Fe, Ni, Mn, Al and Mg in the crucible did not come intocontact with air, the temperature of the crucible was increased to about700˜750° C. inside a resistance heating furnace so that the Fe, Ni, Al,Mn and Mg melted. The crucible was stirred so that the molten Fe, Ni,Al, Mn and Mg were well mixed. The completely molten Mg alloy wascooled, thus preparing an Mg alloy in the solid phase. Also uponcooling, the crucible was immersed in water to enhance the mechanicalstrength of Mg, whereby the molten Mg alloy was rapidly cooled.

The Mg alloy in the solid phase was extruded at 400° C. under conditionsof the ratio of reduction in the cross-sectional area before and afterextrusion (the extrusion ratio) being setto 15:1.

TABLE 1 Ni Al Mn Fe (wt (wt (wt Mg (Fe + Ni)/ (wt part) part) part)part) (wt part) Mn Ex. 1 0.0014 0.0002 0.0021 0.0015 100 2.26 Ex. 20.0092 0.0027 0.0043 0.0380 100 0.313 C. Ex. 1 0.0214 0.0027 0.00530.0036 100 6.69

Test Example 1 Evaluation of Corrosion Rate of Biodegradable ImplantComprising Mg Alloy

The biodegradable implants of Examples 1 and 2 and Comparative Example 1were immersed in a solution having a composition of Table 2 below, andthus the corrosion rate was evaluated based on the hydrogen evolutionamount in relation to the immersion time. The results are shown in FIG.1.

TABLE 2 Molar Concentration [mM/L] Mass [g] CaCl₂ 2H₂O 1.26 0.185 KCl5.37 0.400 KH₂PO₄ 0.44 0.060 MgSO₄•7H₂O 0.81 0.200 NaCl 136.89 8.000Na₂HPO₄ 2H₂O 0.34 0.060 NaHCO₃ 4.17 0.350 D-Glucose 5.55 1.000

With reference to FIG. 1, in Example 1, hydrogen began to occur after 50hours, and in Example 2, hydrogen was not almost generated from initialimmersion to after 200 hours, and thus the implant was slightlycorroded. However, in Comparative Example 1, hydrogen was generated frominitial immersion. Hence, the biodegradation rate of the biodegradableimplants of Examples 1 and 2 satisfying the following condition:0<{Fe+Ni}/Mn≦5 was slower than that of Comparative Example 1 satisfyingthe following condition: {Fe+Ni}/Mn>5

EXAMPLES 3 TO 11 AND COMPARATIVE EXAMPLES 2 TO 5 Manufacturing ofBiodegradable Implant

Mg, Ca, Mn and Zn in the amounts shown in Table 3 below were charged ina crucible having an inner diameter of 50 mm made of stainless steel(SUS 410). Subsequently, while Ar gas was allowed to flow around thecrucible so that Mg, Ca, Mn and Zn in the crucible did not come intocontact with air, the temperature of the crucible was increased to about700˜750° C. inside a resistance heating furnace so that the Mg, Ca, andMn melted. The crucible was stirred so that the molten Mg, Ca, and Mnwere well mixed. The completely molten Mg alloy was cooled, thuspreparing an Mg alloy in the solid phase. Also upon cooling, thecrucible was immersed in water to enhance the mechanical strength of Mg,whereby the molten Mg alloy was rapidly cooled.

The Mg alloy in the solid phase was extruded at 400° C. under conditionsof the ratio of reduction in the cross-sectional area before and afterextrusion (the extrusion ratio) being set to 15:1.

TABLE 3 Mg (wt %) Ca (wt %) Mn (wt %) Zn (wt %) Ex. 3 89 10 1 — Ex. 488.98 9.99 — 1.03 Ex. 5 86.29 10.8 — 2.91 Ex. 6 84.42 10.7 — 4.88 Ex. 794.88 4.62 — 0.50 Ex. 8 94.52 4.72 — 0.76 Ex. 9 93.86 4.51 — 1.63 Ex. 1092.44 4.56 — 3.00 Ex. 11 91.23 4.65 — 4.12 C. Ex. 2 95 5 — — C. Ex. 389.9 10.1 — — C. Ex. 4 100 C. Ex. 5 AZ91: Al: 8.5~9.5%, Zn: 0.45~9%, Mg:the remainder Mg: purity 99.98% Mg, MP21-31-31 (available from TIMMINCO)

Test Example 1 Evaluation of Mechanical Strength of BiodegradableImplant using Mg Alloy

FIG. 2 shows results of evaluating mechanical strength of thebiodegradable implant before extrusion, and FIG. 3 shows results ofevaluating mechanical strength of the biodegradable implant beforeextrusion.

With reference to FIGS. 2 and 3, before extrusion, Example 3 had a yieldstrength of 180 Mpa, which was slightly lower than 220 MPa ofComparative Example 3, and also after extrusion, Example 3 had 280 MPawhich was slightly lower than 320 MPa of Comparative Example 3. However,because 280 MPa is a value that is sufficiently applicable to implantproducts that undergo loads, the corresponding implant may be reasonablyapplied to products. Also, the elongation did not reach 7˜10% beforeextrusion and was increased to 12˜16% after extrusion. This means thatperformance in terms of enduring a strong external impact is superior.

Example 4 had a strength of 170 Mpa which was lower than 220 MPa, butmaintained 320 Mpa equal to that of Comparative Example 3 afterextrusion. The elongation was increased from 12% before extrusion to 17%after extrusion and thus mechanical properties were equal to or betterthan those of Comparative Example 3.

Here, the yield strength refers to the strength at the point in time atwhich the gradient changes in each graph.

Test Example 2: Evaluation of Corrosion Rate of Biodegradable ImplantUsing Mg Alloy

The biodegradable implants of Examples 3 to 11 and Comparative Examples3 to 6 were immersed in a biomimetic solution having a composition ofTable 2, and thus the corrosion rate was evaluated based on the hydrogenevolution rate in relation to the immersion time. This is because thecorrosion rate of an implant is typically determined from the hydrogenevolution rate in the biomimetic solution because hydrogen is generatedupon the biodegradation of Mg.

FIG. 4 is a graph showing the hydrogen evolution rate in relation to theimmersion time in Examples 3 and 4 and Comparative Example 3. FIG. 5 isa graph showing the hydrogen evolution rate in relation to the immersiontime in Examples 4 to 6 before extrusion. FIG. 6 is a graph showing thehydrogen evolution amount in relation to the immersion time in Examples7 to 11 and Comparative Examples 2 and 4 before extrusion. FIG. 7 is agraph showing the hydrogen evolution amount in relation to the Zncontent.

With reference to FIG. 4, in Comparative Example 3, rapid decompositionbegan to occur after 5 hours, but in Example 3 rapid decomposition beganto occur after 17 hours. In Example 4, 30 days after immersion, drasticcorrosion did not take place. Thus the biodegradable implants accordingto the present invention exhibited superior corrosion resistancecompared to Comparative Example 3.

With reference to FIGS. 5 and 6 showing the corrosion rate in relationto the Zn content, the corrosion rate was increased in proportion to anincrease in the Zn content.

With reference to FIG. 7, the corrosion rate in relation to the Zncontent was represented when the hydrogen evolution amount was 0.5ml/cm². In terms of the corrosion rate, the optimal composition of thepresent alloy was 0.118 5% and preferably 0.1˜3%. The reason is that thecorrosion rate zone is the same, but the low Zn content is regarded asgood on the assumption of the same corrosion rate in light of the sideeffects that Zn has on the human body.

On the axis x, 0.5 designates Example 7, 0.76 designates Example 8, 1.63designates Example 9, 3 designates Example 10 and 4.12 designatesExample 11.

FIG. 8 is an electron microscope image showing the surface of theimplant sample of Example 7 immersed in the biomimetic solution for 61hours, and FIG. 9 is an EDS image showing the surface of the implantsample of Example 7. FIG. 10 is an image showing the implant sample ofExample 7 from which the corrosion material was removed.

With reference to FIGS. 8 and 9, the corrosion material was produced onthe surface. The components of the corrosion material are given in Table4 below.

TABLE 4 Component Mass (%) Atom (%) O 33.076 52.0767 Mg 5.580 5.7816 P19.398 15.7781 Ca 41.946 26.3635 Total 100.000 100.0000

As is apparent from Table 4, oxygen was measured as a component of thecorrosion material, from which the implant sample of Example 7 wasoxidized, and phosphorus and calcium were derived from the biomimeticsolution. Thus due to the corrosion material including phosphorus andcalcium, bone binding effects could be increased.

FIG. 10 shows the implant sample from which the corrosion material shownin FIGS. 8 and 9 was removed. The results of analyzing the implantsample of Example 7 having no corrosion material are shown in Table 5below.

TABLE 5 Component Mass (%) Atom (%) O 7.749 11.4133 Mg 90.178 87.4252 P0.521 0.3968 Ca 0.903 0.5305 Zn 0.649 0.2342 Total 100.000 100.0000

With reference to Table 5, even after the corrosion material wasremoved, phosphorus and calcium are left behind. Like this, phosphorusand calcium derived from the biomimetic solution were not easilyremoved.

FIG. 11 is an image showing the cross-section of the implant sample ofExample 7 immersed in the biomimetic solution for 61 hours, FIG. 12 isan enlarged image of the image of FIG. 11, and FIG. 13 is of WDS(AA-8500F, available from JEOL) images showing the implant sample ofExample 7 immersed in the biomimetic solution of Table 2 for 61 hours.

With reference to FIGS. 11 to 13, the bright line region in Mgdesignates Mg₂Ca, and the dark line region designates a corrodedportion. The corrosion was observed to progress while the black linegradually penetrated in Mg.

FIG. 14 is an image showing the cross-section of the implant sample ofExample 8 immersed in the biomimetic solution for 61 hours.

FIG. 15 is of WDS (AA-8500F, available from JEOL) images showing theimplant sample of Example 8 immersed in the biomimetic solution for 61hours.

With reference to FIGS. 14 and 15, Mg₂Ca(Zn) was enclosed with theMg—Ca—Zn compound. When the Zn content was increased, Zn was furthercontained in Mg₂Ca.

Test Example 3 Evaluation of Corrosion Rate of Biodegradable Implantusing Mg Alloy

The yield strength, fracture strength and the elongation of the implantsamples of Examples 7 to 11 and Comparative Example 2 were measured. Theresults are shown in Table 6 below.

TABLE 6 Yield Strength/Fracture Strength Elongation (%) Ex. 7  84 ±3/180 ± 10 11.8 ± 0.4 Ex. 8 107 ± 2/240 ± 15 13.9 ± 1.5 Ex. 9  97 ±2/203 ± 10 9.5 ± 1  Ex. 10 103 ± 2/255 ± 14 12.2 ± 0.6 Ex. 11 109 ±2/247 ± 11 14.6 ± 2  C. Ex. 2  87 ± 3/180 ± 10 10.5 ± 0.3

Test Example 4 Evaluation of Corrosion Rate Upon Applying Ultrasound toBiodegradable Implant Using Mg Alloy

The implant sample of Example 8 was cut to a width of 9.65 cm, a lengthof 19.66 cm, and a thickness of 1.18 cm, thus preparing two samples.Ultrasound was applied to two samples, and then the samples wereimmersed in the biomimetic solution of Table 2 for 3 hours and thehydrogen evolution amount was measured. The results are shown in FIGS.15 and 16.

With reference to FIGS. 16 and 17, the sample to which ultrasound wasapplied generated a large amount of hydrogen, and thus was more quicklycorroded.

EXAMPLES 12 TO 14 Manufacturing of Biodegradable Implant

Mg and Mn in the amounts shown in Table 7 below were Charged in acrucible having an inner diameter of 50 mm that was made of stainlesssteel (SUS 410). Subsequently, while Ar gas was allowed to flow aroundthe crucible so that Mg and Mn in the crucible did not come into contactwith air, the temperature of the crucible was increased to about700˜750° C. inside a resistance heating furnace, so that the Mg and Mnmelted. The crucible was stirred so that the molten Mg and Mn were wellmixed. The completely molten Mg alloy was cooled, thus preparing an Mgalloy in the solid phase. Also upon o cooling, the crucible was immersedin water to enhance the mechanical strength of Mg, whereby the molten Mgalloy was rapidly cooled, resulting in a biodegradable implant.

TABLE 7 Mg (wt %) Mn (wt %) Ex. 12 Remainder 0.0015 Ex. 13 Remainder0.097 Ex. 14 Remainder 0.51 Mg: purity 99.98% Mg, MP21-31-31 (availablefrom TIMMINCO)

Test Example 5 Evaluation of Corrosion Rate of Biodegradable Implant inRelation to Controlled Mn Content

The implant samples of Examples 12 to 14 were cut to a width of 9.65 cm,a length of 19.66 cm, and a thickness of 1.18 cm, thus preparing twosamples. Ultrasound was applied to the two samples, after which thesamples were immersed in the biomimetic solution of Table 2 for 3 hours,and the hydrogen evolution amount was measured. The results are shown inFIG. 18.

With reference to FIG. 18, when Mn was added in an amount of 1 wt % orless but exceeding 0 wt %, corrosion began to occur after 50 hours.Corrosion properties were the most efficiently controlled when Mn wasadded in an amount of 0.5 wt % or more.

Test Example 6 Evaluation of Corrosion Rate of Extruded BiodegradableImplant

The biodegradable implant of Example 14 was extruded at 400° C., and theratio of reduction in the cross-sectional area before and afterextrusion (the extrusion ratio) was set to 25:1.

The biodegradable implant of Example 14 before and after extrusion wasimmersed in the biomimetic solution of Table 2 for 3 hours and thehydrogen evolution amount was measured.

FIG. 19 is of images showing the crystal grains when the biodegradableimplant of Example 14 was not extruded.

With reference to FIG. 19, PCP occurred along the crystal grains.

FIG. 20 is a graph showing corrosion properties of the biodegradableimplant of Example 14 before and after extrusion.

With reference to FIG. 20, when extrusion was not performed, corrosionproperties were deteriorated.

EXAMPLE 15 Manufacturing of Biodegradable Implant

Mg and MgO in the amounts shown in Table 8 below were charged in acrucible having an inner diameter of 50 mm made of stainless steel (SUS410). Subsequently, while Ar gas was allowed to flow around the crucibleso that Mg and MgO in the crucible did not come into contact with air,the temperature of the crucible was increased to about 700˜750° C.inside a resistance heating furnace, so that the Mg and MgO melted. Thecrucible was stirred so that the molten Mg and MgO were well mixed. Thecompletely molten Mg alloy was cooled, thus preparing an Mg alloy in thesolid phase. Also upon cooling, the crucible was immersed in water toenhance the mechanical strength of Mg, whereby the molten Mg alloy wasrapidly cooled, resulting in a biodegradable implant.

TABLE 8 Mg (wt %) MgO (wt %) Ex. 15 Remainder 10 Mg: purity 99.98% Mg,MP21-31-31 (available from TIMMINCO)

Test Example 7 Evaluation of Hydrogen Evolution Amount of BiodegradableImplant Comprising MgO In Vivo

The biodegradable implant samples of Example 15 and Comparative Example4 were inserted into a rat to evaluate the hydrogen evolution amount invivo.

FIG. 21 is a photograph showing the rat having the biodegradable implantsample of Comparative Example 4 inserted therein.

With reference to FIG. 21, hydrogen was generated in the rat, thuscausing swelling.

However, when the biodegradable implant sample of Example 15 wasinserted into the rat, there was no swelling.

1-25. (canceled)
 26. A method of manufacturing a biodegradable implant,comprising: i) providing a magnesium alloy represented by ChemicalFormula 1 below comprising based on total weight thereof, from 4.51 wt %to 10.8 wt % of Ca; from 0.1 to 5 wt % of X, and a remainder of Mg; andii) forming the magnesium alloy:Mg—Ca—X   <Chemical Formula 1> wherein X is Mn or Zn.
 27. The method ofclaim 26, wherein i) comprises: i-1) preparing a porous structure; andi-2) filling pores of the porous structure with the magnesium alloy. 28.The method of claim 26, wherein ii) is performed using one or moreselected from the group consisting of cooling, extrusion, and metalprocessing. 29-36. (canceled)